The present invention relates generally to methods for treating injury or degeneration of retinal ganglion cells by administering glial cell line-derived neurotrophic factor (GDNF) protein product. The invention relates specifically to methods for treating glaucoma or other diseases/conditions involving retinal ganglion cell degeneration.
Neurotrophic factors are natural proteins, found in the nervous system or in non-nerve tissues innervated by the nervous system, that function to promote the survival and maintain the phenotypic differentiation of certain nerve and/or glial cell populations (Varon et al., Ann. Rev. Neuroscience, 1:327, 1979; Thoenen et al., Science, 229:238, 1985). Because of this physiological role, neurotrophic factors are useful in treating the degeneration of such nerve cells and the loss of differentiated function that results from nerve damage. Nerve damage is caused by conditions that compromise the survival and/or proper function of one or more types of nerve cells, including: (1) physical injury, which causes the degeneration of the axonal processes (which in turn causes nerve cell death) and/or nerve cell bodies near the site of injury, (2) temporary or permanent cessation of blood flow (ischemia) to parts of the nervous system, as in stroke, (3) intentional or accidental exposure to neurotoxins, such as the cancer and AIDS chemotherapeutic agents cisplatinum and dideoxycytidine, respectively, (4) chronic metabolic diseases, such as diabetes or renal dysfunction, or (5) neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis, which result from the degeneration of specific neuronal populations. In order for a particular neurotrophic factor to be potentially useful in treating nerve damage, the class or classes of damaged nerve cells must be responsive to the factor. It has been established that all neuron populations are not responsive to or equally affected by all neurotrophic factors.
The first neurotrophic factor to be identified was nerve growth factor (NGF). NGF is the first member of a defined family of trophic factors, called the neurotrophins, that currently includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6 (Thoenen, Trends. Neurosci., 14:165-170, 1991; Snider, Cell, 77:627-638, 1994; Bothwell, Ann. Rev. Neurosci, 18:223-253, 1995). These neurotrophins are known to act via the family of trk tyrosine kinase receptors, i.e., trkA, trkB, trkC, and the low affinity p75 receptor (Snider, Cell, 77:627-638, 1994; Bothwell, Ann. Rev. Neurosci, 18:223-253, 1995; Chao et al., TINS 18:321-326, 1995).
Glial cell line-derived neurotrophic factor (GDNF) is a recently discovered protein identified and purified using assays based upon its efficacy in promoting the survival and stimulating the transmitter phenotype of mesencephalic dopaminergic neurons in vitro (Lin et al., Science, 260:1130-1132, 1993). GDNF is a glycosylated disulfide-bonded homodimer that has some structural homology to the transforming growth factor-beta (TGF-.beta.) super family of proteins (Linet al., Science, 260:1130-1132, 1993; Krieglstein et al., EMBO J., 14:736-742, 1995; Poulsen et al., Neuron, 13:1245-1252, 1994). GDNF mRNA has been detected in muscle and Schwann cells in the peripheral nervous system (Henderson et al., Science, 266:1062-1064, 1994; Trupp et al., J. Cell Biol., 130:137-148, 1995) and in type I astrocytes in the central nervous system (Schaar et al., Exp. Neurol., 124:368-371, 1993). In vivo, treatment with exogenous GDNF stimulates the dopaminergic phenotype of substantia nigra neurons and restores functional deficits induced by axotomy or dopaminergic neurotoxins in animal models of Parkinson's disease (Hudson et al., Brain Res. Bull., 36:425-432, 1995; Beck et al., Nature, 373:339-341, 1995; Tomac et al., Nature, 373:335-339, 1995; Hoffer et al., Neurosci. Lett., 182:107-111, 1994). Although originally thought to be relatively specific for dopaminergic neurons, at least in vitro, evidence is beginning to emerge indicating that GDNF may have a larger spectrum of neurotrophic targets besides mesencephalic dopaminergic and somatic motor neurons (Yan and Matheson, Nature 373:341-344, 1995; Oppenheimet al., Nature, 373:344-346, 1995; Matheson et al., Soc. Neurosci. Abstr, 21, 544, 1995; Trupp et al., J. Cell Biol., 130:137-148, 1995). In particular, GDNF was found to have neurotrophic efficacy on brainstem and spinal cord cholinergic motor neurons, both in vivo and in vitro (Oppenheim et al., Nature, 373:344-346, 1995; Zurn et al., Neuroreport, 6:113-118, 1994; Yan et al., Nature, 373: 341-344, 1995; Henderson et al., Science, 266:1062-1064, 1994).
Of general interest to the present invention is WO93/06116 (Lin et al., Syntex-Synergen Neuroscience Joint Venture), published Apr. 1, 1993, which reports that GDNF is useful for the treatment of nerve injury, including injury associated with Parkinson's disease. Also of interest are a report in Schmidt-Kastner et al., Mol. Brain Res., 26:325-330, 1994 that GDNF mRNA became detectable and was upregulated after pilocarpine-induced seizures; reports in Schaar et al., Exp. Neurol., 124:368-371, 1993 and Schaar et al., Exp. Neurol., 130:387-393, 1994 that basal forebrain astrocytes expressed moderate levels of GDNF mRNA under culture conditions, but that GDNF did not alter basal forebrain ChAT activity; and a report in currently pending U.S. application Ser. No. 08/535,682 filed Sep. 28, 1995 that GDNF is useful for treating injury or degeneration of basal forebrain cholinergic neurons. GDNF has not previously been shown to promote survival or regeneration of injured retinal ganglion cells.
Retinal ganglion cells play a major role in visual perception, which occurs in several stages. First, light is converted into electrical signals by specialized neurons, called photoreceptors, which are located in the outer layers of the retina. These signals are then combined and transmitted by interneurons to the retinal ganglion cells, located in the inner layer of the retina, which then relay this information to the visual cortex region of the brain. The retinal ganglion cell axons converge to form the optic nerve, which projects to the lateral geniculate nucleus and to the superior colliculus in the brain, as well as to brainstem nuclei.
Damage to retinal ganglion cells is the primary injury seen in glaucoma, which is the third most prevalent cause of blindness. Glaucoma is the term used for a group of disorders characterized by an optic neuropathy involving the progressive loss of retinal ganglion cells. This damage to retinal ganglion cells is characterized by axonal transport dysfunction and histopathologic abnormalities of the axons within the optic nerve head, and is associated with a typically excavated appearance of the optic nerve head. Optic nerve degeneration can also result from other conditions of the optic disc, e.g., papilledema due to increased intracranial pressure, papillitis (a form of optic neuritis) or ischemia.
In most cases of glaucoma, the optic nerve damage is caused by elevated intraocular pressure. The major types of glaucoma associated with elevated intraocular pressure are open-angle, angle-closure and secondary glaucomas. In some cases of glaucoma, a similar excavation of the nerve head occurs despite a normal intraocular pressure range. In all cases, higher intraocular pressures are generally associated with greater nerve damage. Glaucoma is usually treated by attempting to lower the intraocular pressure, either medically or surgically.
Chronic open-angle glaucoma is the most common type and is seen in about 0.5% of American and European adults. In this type of glaucoma, there is a blockage to the resorption of aqueous humor inside the eye, causing the intraocular pressure to rise above its normal maximum of 21 mm Hg and to gradually destroy the axons and supporting tissue in the optic disc. This type of glaucoma is ordinarily asymptomatic until well advanced. Initial visual loss is seen in the peripheral field of vision. Diagnosis is made by measurements of intraocular pressure, examination of the optic disc, and testing of the patient's visual fields. Treatment is primarily medical, by topical administration of parasympathomimetics (pilocarpine and carbachol), beta-adrenergic blockers (timolol) and sympathomimetics (epinephrine) which act to decrease intraocular pressure. When these medications, individually or in combination, no longer arrest the progressive damage, indirect parasympathomimetics (echothiophate) and carbonic anhydrase inhibitors (acetazolamide and methazolamide) are prescribed. If medical therapy fails, surgical treatment can be performed to open outflow channels. A subset of open-angle glaucoma is congenital, resulting from the developmental failure of certain anatomical structures in the eye.
In angle-closure glaucoma, the outflow of aqueous humor is mechanically impeded owing to a shallow anterior chamber. The intraocular pressure remains normal until a pupillary block (causing resistance to aqueous flow through the pupil) obstructs the resorptive surfaces in the angle. The pressure then rises precipitously, often to above 50 mm Hg. This glaucoma is generally monocular and is characterized by a red and painful eye, a fixed and dilated pupil, decreased vision, sweating and nausea. An acute attack is a medical emergency and is treated with parenteral acetazolamide, oral glycerol or intravenous mannitol, and topical administration of pilocarpine and sometimes timolol. After the acute attack is managed, the anatomic problem can be eliminated by surgery.
Secondary glaucoma develops as a consequence of another ocular disease. Examples are glaucoma precipitated by swelling of the lens, neovascularization (formation of new blood vessels) in the angle structures, chronic inflammation, or severe blunt trauma to angle structures. The treatment for secondary lens-induced glaucoma is surgical removal of the lens. Most other secondary glaucomas are managed medically in the same way as primary open-angle glaucoma. Neovascular glaucoma is difficult to treat, but may be improved with laser photocoagulation.
There continues to exist a need for methods and therapeutic compositions useful for the treatment of retinal ganglion cell injury associated with conditions such as glaucoma. Such methods and therapeutic compositions would ideally protect the retinal ganglion cells and optic nerve from progressive injury and promote survival or regeneration of the damaged neurons, without severe adverse side effects.